PubMed · 10728480
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1999. SPC 3.. https://doi.org/10.2165/00126839-199902050-00018
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BACKGROUND: HIV proviral sequencing overcomes the limit of plasma viral load requirement by detecting all the 'archived mutations', but the clinical relevance remains to be evaluated. METHODS: We included 25 participants with available proviral sequences (both intact and defective sequences available) and utilized the genotypic sensitivity score (GSS) to evaluate the level of resistance in their provirus and plasma virus. Defective sequences were further categorized as sequences with and without hypermutations. Personalized GSS score and total GSS score were calculated to evaluate the level of resistance to a whole panel of antiretroviral therapies and to certain antiretroviral therapy that a participant was using. The rate of sequences with drug resistance mutations (DRMs) within each sequence compartment (intact, defective and plasma viral sequences) was calculated for each participant. RESULTS: Defective proviral sequences harbored more DRMs than other sequence compartments, with a median DRM rate of 0.25 compared with intact sequences (0.0, P = 0.014) and plasma sequences (0.095, P = 0.30). Defective sequences with hypermutations were the major source of DRMs, with a median DRM rate of 1.0 compared with defective sequences without hypermutations (0.042, P < 0.001). Certain Apolipoprotein B Editing Complex 3-related DRMs including reverse transcriptase gene mutations M184I, E138K, M230I, G190E and protease gene mutations M46I, D30N were enriched in hypermutated sequences but not in intact sequences or plasma sequences. All the hypermutated sequences had premature stop codons due to Apolipoprotein B Editing Complex 3. CONCLUSION: Proviral sequencing may overestimate DRMs as a result of hypermutations. Removing hypermutated sequences is essential in the interpretation of proviral drug resistance testing.
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The 4-aminoquinoline chloroquine and its analogue hydroxychloroquine are endowed with anti-HIV-1 activity both in vitro and in vivo. We previously reported that the addition of CQ (chloroquine) to the combination of HU (hydroxyurea) and ddI (didanosine) provides additive anti-HIV-1 activity. We here extended this in vitro investigation by studying whether the addition of CQ also resulted in additive anti-HIV-1 activity when combined with HU plus AZT (zidovudine). The same effect was found, whether CQ was added to HU plus AZT or to HU plus ddI, in recently infected H-9 and U-937 cells or primary T cells and monocytes, as well as in immunologically or oxidatively stimulated ACH-2 and U-1 cells. At concentrations where CQ exerts its anti-HIV-1 effect in combination with the other drugs, CQ addition does not result in either cell toxicity or apoptosis.